The present invention relates to compounds that suppress cholesterol biosynthesis in humans by competitively inhibiting 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase and, more particularly, to processes for preparing pharmaceutically appropriate salts for oral administration of such compounds.
[R(R*,R*)]-2-(4-fluorophenyl)-xcex2,xcex4-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid (xe2x80x9catorvastatinxe2x80x9d) is an inhibitor of cholesterol biosynthesis in humans. It is one of a class of drugs called statins. Statins suppress cholesterol biosynthesis by competitively inhibiting 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (xe2x80x9cHMG-CoA reductasexe2x80x9d). HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonate, which is the rate determining step in the biosynthesis of cholesterol. Goodman and Gilman, The Pharmacological Basis of Therapeutics 841 (MacMillan Publ. Co.: New York 7th ed. 1985). Decreased production of cholesterol stimulates LDL receptor activity and consequently reduces the concentration of LDL particles in the bloodstream. Reducing LDL concentration in the bloodstream decreases the risk of coronary artery disease J.A.M.A. 1984, 251, 351-74.
Racemic trans-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-tetrahydro-4-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-carboxamide (xe2x80x9cthe racemic atorvastatin lactonexe2x80x9d) was reported to be a useful inhibitor of cholesterol biosynthesis in U.S. Pat. No. 4,681,893, in 1987. The racemic lactone was synthesized according to the chemical process summarized in Scheme 1. 
Example 2 of the ""893 patent describes the preparation of the sodium salt of (R*,R*) -2-(4-fluorophenyl)-xcex2,xcex4-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid (xe2x80x9cracemic atorvastatin sodiumxe2x80x9d) by treating the racemic lactone with sodium hydroxide in THF:water, as shown in Scheme 2. 
U.S. Pat. No. 5,273,995 discloses atorvastatin, the pure [R(R*,R*)] enantiomer of 2-(4-fluorophenyl)-xcex2,xcex4-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid. The ""995 patent describes a stereoselective preparation (Scheme 3) of atorvastatin wherein the absolute configuration of the side chain hydroxy group closest to the pyrrole ring is set by a stereoselective aldol condensation. After chain extension with tert-butyl acetate, reduction of the xcex2 ketone proceeds under substrate stereocontrol to orient the xcex2 hydroxy group cis to the xcex4 hydroxy group. 
The ""995 patent describes a preparation of atorvastatin hemi-calcium, which is the salt form of the drug that has been approved by the U.S. Food and Drug Administration for oral administration to human patients. To prepare atorvastatin hemi-calcium, the ""995 patent teaches that the sodium salt is prepared first by dissolving the lactone in methanol and water and adding a little less than one equivalent of sodium hydroxide to the solution until the lactone has been opened as determined by high performance liquid chromatography (HPLC). The ""995 patent then teaches that the hemi-calcium salt may be prepared from the sodium salt by treating it with one equivalent or a slight excess of calcium chloride dihydrate (CaCl2.2H2O) (steps d and e of Scheme 3). To an atorvastatin sodium salt solution whose exact concentration has been determined by HPLC is slowly added an equivalent or slight excess of CaCl2.2H2O at elevated temperature while agitating the solution. After completing the addition, atorvastatin hemi-calcium is obtained as a precipitate by cooling the solution. The ""995 patent also describes how the pure R,R stereoisomer may be obtained from a mixture of R,R and S,S stereoisomers obtained from the ""893 patent process.
U.S. Pat. No. 5,298,627 discloses an improved, more convergent, process for preparing atorvastatin in which the side chain bearing the xcex2,xcex4-dihydroxy carboxylic acidxe2x80x94which is essential for biological activityxe2x80x94is incorporated in a single step (Scheme 4) rather than being elaborated from a propanal side chain as disclosed in the ""893 and ""995 patents. 
The convergent step of the process is a Paal Knorr reaction (step e). After the convergent step, the acetonide protecting group on the xcex2 and xcex4 hydroxyls is cleaved with acid (step f). The ""627 patent teaches that the sodium salt may be prepared from the N,N-diphenyl amide without intermediate isolation of the lactone by treating it with sodium hydroxide in a mixture of methanol and water (step g). The hemi-calcium salt is then prepared by dissolving the sodium salt in a solution of calcium acetate (Ca(OAc)2) at room temperature and crystallizing the hemi-calcium salt from the solution by cooling. The ""627 patent also describes preparations in which other N,N-disubstituted acetamides are used in the first step in otherwise similar processes. The ""627 process is said to be well adapted for large scale production of atorvastatin.
Brower, P. L. et al. Tet. Lett. 1992, 33, 2279-82 states that (4R-cis)-1,1-dimethylethyl-6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate is an ideal intermediate for preparing atorvastatin because it is highly crystalline and readily obtainable by recrystallization in high purity. After extensive optimization of the Paal-Knorr reaction, atorvastatin hemi-calcium was prepared from the highly crystalline intermediate in 60% yield following a procedure generally similar to steps (d) through (h) of Scheme 4. Baumann, K. L. et al. Tet. Lett. 1992, 33, 2283-2284. Conversion of the Paal Knorr reaction product to atorvastatin hemi-calcium was carried out without isolation of intermediate products by deprotection of the acetonide with aqueous HCl/methanol, dilute base hydrolysis of the tert-butyl ester (anchimeric assistance) and treatment of the derived sodium salt with Ca(OAc)2 as shown in Scheme 5. As in the process of the ""627 patent previously described, the carboxyl protecting group was cleaved with sodium hydroxide and atorvastatin hemi-calcium was prepared by treating the sodium salt with calcium acetate. 
U.S. Pat. Nos. 5,003,080; 5,097,045; 5,124,482; 5,149,837; 5,216,174; 5,245,047 and 5,280,126 disclose methods of making atorvastatin free acid and lactone and/or stereoisomers thereof. Roth, B. D. et al. J. Med. Chem. 1991, 34, 357-66 discloses preparations of atorvastatin lactone and other pyrrol-1-yl ethylmevalonolactones with variable substituents on the pyrrole ring.
Kearney, A. S. et al. xe2x80x9cThe Interconversion Kinetics, Equilibrium, and Solubilities of the Lactone and Hydroxyacid Forms of the HMG-CoA Reductase Inhibitor, CI-981xe2x80x9d Pharm. Res. 1993, 10, 1461-65 reports that the carboxylic acid group of atorvastatin has a PKa of 4.46. The acidic proton of the carboxylic acid group of intermediate compounds used to prepare atorvastatin by the ""893 and ""995 patent processes must be masked during the chain elaboration steps. The carboxyl group is also protected during the Paal Knorr reaction in the ""627 patent and Baumann et al. processes. Forming an ester is a well known way of protecting a carboxylic acid group and masking its acidic proton. Green, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis 3rd. ed., chapter 5 (John Wiley and Sons: New York 1999) (xe2x80x9cGreene and Wutsxe2x80x9d). It is also known, generally, that carboxylic acids that have been protected as esters may be deprotected by hydrolyzing the ester with a strong base. Id. at 377-78.
Sodium hydroxide is a strong base with a dissociation constant of 6.37 (pKb=xe2x88x920.80), Handbook of Chemistry and Physics 81st ed. 8-45 (CRC Press: Boca Raton 2000xe2x88x9201), and its use as a reagent for deprotecting ester-protected carboxylic acids is taught in the art. Green and Wuts, p. 377. Calcium hydroxide (Ca(OH)2), with a first dissociation constant of 3.74xc3x9710xe2x88x923 (pKb=2.43) and second dissociation constant of 4.0xc3x9710xe2x88x922 (pKb=1.40), is a much weaker base than sodium hydroxide. Handbook of Chemistry and Physics 63rd ed. D-170 (CRC Press: Boca Raton 1983).
Calcium hydroxide is not listed among the reagents that have been used to hydrolyze esters in a well known compendium of functional group transformations in organic synthesis. Larock R. C. Comprehensive Organic Transformations 2nd ed, Section Nitriles, Carboxylic Acids and Derivatives, Sub-sect. 9.17, pp. 1959-68 (Wiley-VCH: New York 1999). Its use as a general reagent for deprotecting ester-protected carboxylic acids is not taught by a well known reference book on methods for protecting and deprotecting organic functional groups. Greene and Wuts. pp. 377-79. In fact, the ""995 patent cautions against using an excess of sodium hydroxide to prepare the sodium salt in order to prevent forming calcium hydroxide when calcium chloride is later added to a solution of the sodium salt. It appears not to have been appreciated that an ester-protected form of atorvastatin can be converted directly to atorvastatin hemi-calcium without first treating the ester with a strong base like sodium hydroxide to hydrolyze it.
The present invention meets a long-felt need for a more direct, practicable, convenient and high yielding route to atorvastatin hemi-calcium from a carboxylic acid ester derivative of atorvastatin.
It has now been discovered that an atorvastatin carboxylic acid ester derivative can be converted directly to atorvastatin hemi-calcium with calcium hydroxide. The calcium hydroxide performs two functions. It is a basic catalyst for hydrolyzing the carboxylic acid ester and it supplies calcium ion to coordinate with atorvastatin carboxylate anions to form atorvastatin hemi-calcium.
Accordingly, the present invention provides a process for preparing atorvastatin hemi-calcium by converting an atorvastatin ester derivative of formula: 
wherein R1 is a lower alkyl group, to atorvastatin hemi-calcium with calcium hydroxide.
The process is advantageously practiced in a process provided by this invention for converting a dioxanyl derivative of atorvastatin of formula: 
wherein R1 is as previously defined, to atorvastatin hemi-calcium, hereafter referred to as the sequential acid-base hydrolysis process. The sequential acid-base hydrolysis process may be conveniently practiced by following one of the exemplary embodiments.
In one exemplary embodiment, the sequential acid-base hydrolysis process is performed in two steps with intermediate isolation of an atorvastatin ester derivative. The isolated atorvastatin ester derivative may be the direct product of hydrolysis of the dioxane and have the structural formula 1. Another atorvastatin ester derivative resulting from ester transposition with an alcohol solvent and/or atorvastatin lactone may also be obtained, optionally in mixture with some atorvastatin free acid. First, the dioxane 2 is converted to one or more of these atorvastatin ester derivatives with an acid catalyst, preferably acetic acid. The atorvastatin ester derivative or mixture thereof is then isolated in condensed form, i.e. as a solid or oil. Second, the isolated atorvastatin ester derivative(s) is converted to atorvastatin hemi-calcium with calcium hydroxide and, optionally, a phase transfer agent.
In another exemplary embodiment, dioxane 2 is hydrolyzed in a mixture of an acid catalyst and a mixed solvent comprising a C1-C4 alcohol of formula R2xe2x80x94OH and water to form the atorvastatin ester derivative 1 or another atorvastatin ester derivative, optionally in mixture with some atorvastatin free acid. The ester derivative(s) is then converted to atorvastatin hemi-calcium with calcium hydroxide in a solution of a C1-C4 alcohol. The steps of the second embodiment of the sequential acid-base hydrolysis process are advantageously practiced in a single reaction vessel, i.e. as a xe2x80x9cone-potxe2x80x9d process. In either embodiment of the acid-base process, atorvastatin hemi-calcium, or a solvate thereof, may be separated from the solvent and dissolved substances by precipitation.
Some of the terms used in this disclosure have the following ascribed meanings.
A C1-C4 alcohol is a compound of the formula R2xe2x80x94OH wherein R2 is methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl or t-butyl.
An xe2x80x9cester derivativexe2x80x9d is a compound resulting from replacement of the hydroxyl proton of a carboxylic acid with a substituent bonded to the hydroxyl oxygen atom through carbon. Unless otherwise excluded by a formula, an ester derivative includes a lactone, which is a cyclic ester in which the ester group in incorporated into a ring. Ester derivatives also include compounds where the substituent bonded to the hydroxyl oxygen is C1-C4 alkyl group.
In its first aspect, the present invention provides a process for preparing atorvastatin hemi-calcium by converting an atorvastatin ester derivative of formula: 
wherein R1 is a C1 to C4 alkyl, to atorvastatin hemi-calcium with calcium hydroxide. An unexpected advantage of this process is that the calcium hydroxide fulfills two roles. It functions as a basic catalyst for hydrolysis of the ester and supplies calcium ion that coordinates to atorvastatin anions. Another significant practical advantage of the process is that the amount of calcium hydroxide does not have to be as carefully controlled as the amount of sodium hydroxide and calcium chloride used in other processes.
The atorvastatin ester derivative 1 may be provided in pure form or in mixture with other atorvastatin ester derivatives. In a second aspect of the invention, described below, a mixture of intermediate atorvastatin ester derivatives are formed from a dioxanyl precursor compound. These atorvastatin ester derivatives include, in addition to those of formula 1, those derived from transposition of atorvastatin ester derivative 1 with a C1-C4 alcohol solvent of formula R2xe2x80x94OH. In addition, atorvastatin ester derivative 1 may be provided in mixture with atorvastatin lactone, which may form from atorvastatin free acid, small amounts of which are in equilibrium with the ester in the acidic aqueous solvents used in the second aspect of this invention.
In the invention""s first aspect, hereafter referred to as the base hydrolysis process, the atorvastatin ester derivative 1, optionally in mixture with other atorvastatin ester derivatives, is dissolved or suspended in a mixed solvent comprising a C1-C4 alcohol and water. A preferred alcohol is ethanol and a preferred solvent mixture contains about 5% to about 15% water in ethanol, more preferably about 10% water and about 90% ethanol (v/v). Whether the atorvastatin ester derivative 1 dissolves in the mixed solvent depends upon such factors as the choice of C1-C4 alcohol, the proportion of water, the temperature and the purity of the atorvastatin ester derivative. Calcium hydroxide is suspended in the mixed solvent and the base hydrolysis reaction mixture is maintained until the atorvastatin ester derivative 1 has been consumed. Consumption of atorvastatin ester derivative 1 may be monitored by any conventional means like TLC, HPLC, NMR and the like. After the atorvastatin ester derivative 1 has been consumed, atorvastatin hemi-calcium is recovered from the base hydrolysis reaction mixture by any means. It is unnecessary to add another source of calcium to provide a Ca2+ ion for the atorvastatin hemi-calcium salt.
According to a preferred procedure for practicing the base hydrolysis process, the atorvastatin ester derivative 1 is added in an amount sufficient to provide about 10 mmoles Lxe2x88x921  to about 1 mole Lxe2x88x921  of the mixed solvent.
Preferably, about 1 equivalent to about 6 equivalents of calcium hydroxide with respect to the ester derivative 1 is used. More preferably, from about 1 to about 2 equivalents is used.
Calcium hydroxide is only sparingly soluble in the C1-C4 alcohol:water mixed solvent and only a minor proportion of it will be in solution available to catalyze the hydrolysis at any one time. To accelerate the base hydrolysis, a phase transfer catalyst may be added to increase the solubility of the calcium hydroxide. Phase transfer catalysts are well known in the art and include, for instance, tetra-n-butylammonium bromide (xe2x80x9cTBABxe2x80x9d), benzyltriethylammonium chloride (xe2x80x9cTEBAxe2x80x9d), tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, tetra-n-butylammonium iodide, tetra-ethylammonium chloride, benzyltributylammonium chloride, benzyltributylammonium bromide, benzyltriethylammonium bromide, tetramethylammonium chloride and polyethylene glycol. A most preferred phase transfer catalyst is TBAB. When used, the phase transfer catalyst should be used in a substoichiometric amount, preferably from about 0.05 to about 0.25 equivalents, more preferably about 0.1 equivalents, with respect to atorvastatin ester derivative 1.
The mixture may be heated to up to the reflux temperature of the mixed solvent in order to accelerate the reaction. A preferred temperature range is from about 30xc2x0 C. to about 70xc2x0 C.
After consumption of atorvastatin ester derivative 1, atorvastatin hemi-calcium or solvate thereof is recovered from the base hydrolysis reaction mixture. As part of recovering the atorvastatin hemi-calcium, the reaction mixture should be filtered to remove excess suspended calcium hydroxide. The reaction mixture preferably is filtered hot to prevent precipitation of atorvastatin hemi-calcium on the calcium hydroxide filtercake.
After filtration to remove suspended calcium hydroxide, atorvastatin hemi-calcium may be recovered from the filtrate by precipitation. According to a preferred recovery technique, atorvastatin hemi-calcium is caused to precipitate from the filtrate by slow addition of water. A volume of water roughly equivalent to the volume of the filtrate is added over about an hour""s time. Preferably, the slow water addition is also conducted at elevated temperature, e.g from about 40xc2x0 C. to about 65xc2x0 C. Precipitating atorvastatin hemi-calcium by slow water addition yields atorvastatin hemi-calcium in a crystalline trihydrate state and prevents formation of a gelatinous precipitate. Alternatively, atorvastatin hemi-calcium may be recovered by any conventional means. After any necessary purification steps, the recovered atorvastatin hemi-calcium may be used as an active ingredient to formulate a pharmaceutical product.
In a second aspect of the invention, the base hydrolysis process for converting atorvastatin ester derivative 1 to atorvastatin hemi-calcium is preceded by acid hydrolysis of a dioxane of formula: 
wherein R1 is as previously defined. This two-step process (which may be conducted in single reaction vessel) is hereafter referred to as the sequential acid-base hydrolysis process.
Dioxane 2 is an important intermediate in the preparation of atorvastatin. For example, it is an intermediate in the Baumann et al. process. Dioxane 2 is a protected form of atorvastatin with an acetonide protecting group on the xcex2,xcex4-dihydroxy groups and an ester group masking the carboxylic acid proton.
According to one preferred embodiment of the sequential acid-base hydrolysis process, dioxane 2 is converted into an atorvastatin ester derivative or mixture thereof, which is then isolated as a solid or oil before being carried forward to prepare atorvastatin hemi-calcium according to the base hydrolysis process of the invention. In this embodiment, the dioxane ring of dioxane 2 is cleaved with a catalyst selected from the group consisting of acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, zinc bromide and hydrochloric acid. Procedures for practicing this process using these catalysts are illustrated in Example 1. In its most preferred mode, this embodiment uses acetic acid as an 80% solution in water (Example 1 (a)-(c)). Dioxane 2 is suspended in the aqueous acetic acid and stirred at room temperature until a clear solution is obtained. The acetic acid is then evaporated under reduced pressure. Remaining traces of acetic acid may be removed by azeotroping with toluene, leaving a residue of atorvastatin ester derivative 1 as a solid or as a viscous oil containing residual toluene. The residue may also contain amounts of atorvastatin lactone and atorvastatin free acid.
As further illustrated in Example 2, the residue may be converted to atorvastatin hemi-calcium by suspending in the C1-C4 alcohol:water mixed solvent and adding from about 1 to about 6, more preferably in this embodiment from about 4 to about 6 equivalents of calcium hydroxide and a phase transfer agent. After the atorvastatin ester derivative 1 has been consumed, the mixture is filtered to remove excess calcium hydroxide. Atorvastatin hemi-calcium or solvate thereof may then be recovered by precipitation, e.g., by cooling the solution and/or adding water (for example as previously described for the base hydrolysis process), filtering and drying. The filtrate also may be further purified by recrystallization using known techniques or by chromatography.
In another preferred embodiment of the sequential acid-base hydrolysis process, both the acid hydrolysis of the 1,3-dioxane ring of dioxane 2 and the subsequent base hydrolysis of the ester are performed in a mixed solvent of a C1-C4 alcohol and water. Thus, this embodiment of the sequential acid-base hydrolysis process may be advantageously practiced entirely in one reaction vessel without a change of solvent or isolation of an atorvastatin ester intermediate or mixture of intermediates. An additional advantage of this xe2x80x9cone-potxe2x80x9d embodiment is that it enables further reduction of the amount of calcium hydroxide used, yet without demanding strict adherence to a predetermined exact molar ratio. The one-pot embodiment also does not involve using a phase transfer agent and uses a mineral acid to cleave the 1,3 dioxane ring, thus reducing the cost of reagents.
In the one-pot embodiment of the sequential acid-base hydrolysis process, dioxane 2 is suspended in the mixed alcohol:water solvent in a vessel that is able to withstanding a vacuum and is equipped with a heater and a distillation head. The mixed solvent is pH adjusted to about 1 or less with hydrochloric acid or other mineral acid. Hydrochloric acid is preferred because a small amount of calcium chloride is formed when calcium hydroxide is added to the reaction mixture. Calcium chloride is readily soluble in the mixed solvent and therefore easily separated from the product when atorvastatin hemi-calcium is precipitated from the reaction mixture. The mixed solvent is conveniently prepared and pH adjusted by mixing dilute aqueous hydrochloric acid with the C1-C4 alcohol, from 1.5% to 10% hydrochloric acid being preferred.
Dioxane 2 is preferably added in an amount of about 0.12 moles Lxe2x88x921  of the C1-C4 alcohol. The resulting suspension may be heated to accelerate hydrolysis of the dioxane. Preferred temperatures for the hydrolysis are mildly elevated, ranging from about 30xc2x0 C. to about 50xc2x0 C., more preferably about 40xc2x0 C.
Under acidic aqueous conditions, the dioxane 2 and free diol 1 are in equilibrium. Under the preferred reaction conditions, the mixed solvent contains something on the order of a ten fold molar excess of water over the amount of acetone that would be produced by complete hydrolysis. A significant amount of the dioxane would remain in the reaction mixture if acetone were not removed. Therefore, it is desirable to remove acetone that is liberated by the acid hydrolysis from the reaction vessel by evaporation To meet this purpose at the preferred reaction temperatures, the reaction vessel should be maintained under sufficiently reduced pressure to distill off the liberated acetone. Aspirator vacuum is generally sufficient. Alcohol and water vapors may be drawn off by the distillation head along with the acetone. Make up alcohol may be added to the mixture to maintain a constant volume. Consumption of dioxane 2 may be monitored by HPLC chromatography, or by observing the formation of a clear solution and allowing a period of about 9 to 11 hrs for consumption of dissolved dioxane 2.
Acid hydrolysis of dioxane 2 produces atorvastatin ester derivative 1 as a direct product. However, other reactions occur to a greater or lesser extent under these conditions. Transesterification occurs with the alcohol solvent component to form atorvastatin ester derivatives of formula: 
wherein R2 is the alkyl substituent of the C1-C4 alcohol, and may be the same or different from R1. In the presence of water, some atorvastatin free acid forms. The free acid in turn lactonizes, although a proportion remains in equilibrium as the free acid with the lactone and with the other atorvastatin ester derivatives.
After dioxane 2 has been completely consumed, calcium hydroxide is added to the resulting solution. The rate of hydrolysis of the atorvastatin ester derivatives by calcium hydroxide depends upon a variety of factors including the temperature, concentration of the ester derivatives in the mixture, the exact composition of the mixture, all of which can vary in accordance with the invention. The rate of hydrolysis also depends upon the quantity and particle size of the calcium hydroxide used. With these considerations in mind, an optimal set of base hydrolysis conditions using calcium hydroxide has been developed.
The total atorvastatin ester derivative concentration, which is taken as equal to the concentration of dioxane 2, is adjusted to from about 0.10 to about 0.15 M, by continuing to distill solvent or by adding more C1-C4 alcohol and/or water. Any amount of calcium hydroxide in excess of about xc2xe molar equivalent with respect to the dioxane 2 may be used. However, in the one-pot embodiment of the sequential acid-base hydrolysis process, preferably from about 1 to about 2 equivalents, more preferably about 1.5 molar equivalents of calcium hydroxide with respect to the atorvastatin ester derivatives (or dioxane 2) is used. Calcium hydroxide may be added in one or more than one portion. Further, the reaction mixture is preferably heated to from about 50xc2x0 C. to about 70xc2x0 C., more preferably about 70xc2x0 C. Under these conditions, the atorvastatin ester derivative(s), i.e. compound 1, transposed ester 3, and atorvastatin lactone are substantially completely hydrolyzed within a few hours. The consumption of the atorvastatin ester derivatives may be monitored by HPLC. Using these conditions, atorvastatin hemi-calcium can be later precipitated from the base hydrolysis reaction mixture substantially free of impurities, i.e. containing less than 0.05%, atorvastatin ester derivative 1.
After the atorvastatin ester derivatives have been consumed, excess suspended calcium hydroxide should be filtered from the mixture if it is desired to precipitate atorvastatin hemi-calcium from the base hydrolysis reaction mixture with minimal contamination by calcium hydroxide. The reaction mixture preferably is filtered hot to prevent precipitation of atorvastatin hemi-calcium on the calcium hydroxide filtercake. Using the preferred amount of 1 to 2 equivalents of calcium hydroxide in the one-pot process also minimizes losses due to precipitation of atorvastatin hemi-calcium on the calcium hydroxide filter cake and increases the purity of the atorvastatin hemi-calcium recovered from the solution by precipitation.
Further, according to the preferred mode of practicing the one-pot sequential acid-base hydrolysis process, atorvastatin hemi-calcium is caused to precipitate from the filtrate by slow addition of water as previously described with reference to the base hydrolysis process. The precipitate may be carried forward and used in a pharmaceutical product.
The filtering characteristics and purity of the atorvastatin hemi-calcium may be further improved by redissolving the crystalline product in the aqueous alcohol reaction mixture by heating to a temperature sufficient to cause all the precipitate to dissolve, resulting in a clear solution. The solution should then be slowly cooled over several hours and held, preferably at ambient temperature, until no more crystals are observed to form. After filtering and drying, and any necessary purification steps, the atorvastatin hemi-calcium or solvate thereof may be used as an active ingredient in a pharmaceutical product.
Having thus described the present invention with reference to certain of its preferred embodiments, it will now be further illustrated with the following examples which offer highly specific procedures that may be followed in practicing the invention but which should not be construed as limiting the invention in any way.